Arcangelo Giurioli

Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial

BACKGROUND The rationale for combining anticancer drugs has not been applied consistently to use of intravesical agents for treatment of superficial bladder cancer, for which immunotherapeutic BCG and chemotherapeutic mitomycin seem to be a potentially effective combination. We aimed to do a prospective, randomised comparison of BCG alone with that of sequential BCG and electromotive mitomycin in patients with stage pT1 bladder cancer. METHODS After transurethral resection and multiple biopsies, 212 patients with stage pT1 bladder cancer were randomly assigned to: 81 mg BCG infused over 120 min once a week for 6 weeks (n=105); or to 81 mg BCG infused over 120 min once a week for 2 weeks, followed by 40 mg electromotive mitomycin (intravesical electric current 20 mA for 30 min) once a week as one cycle for three cycles (n=107). Complete responders underwent maintenance treatment: those assigned BCG alone had one infusion of 81 mg BCG once a month for 10 months, and those assigned BCG and mitomycin had 40 mg electromotive mitomycin once a month for 2 months, followed by 81 mg BCG once a month as one cycle for three cycles. The primary endpoint was disease-free interval; secondary endpoints were time to progression; overall survival; and disease-specific survival. Analyses were done by intention to treat. This trial has been submitted for registration at the US National Cancer Institute website . FINDINGS Median follow-up was 88 months (IQR 63-110). Patients assigned sequential BCG and electromotive mitomycin had higher disease-free interval than did those assigned BCG alone (69 months [95% CI 55-86] vs 21 months [15-54]; difference between groups 48 months [42-54], log-rank p=0.0012). Patients assigned sequential BCG and electromotive mitomycin also had lower recurrence (41.9% [32.7-51.5] vs 57.9% [48.7-67.5]; difference between groups 16.0% [2.7-29.3], log-rank p=0.0012); progression (9.3% [3.8-14.8] vs 21.9% [17.9-25.9]; difference between groups 12.6% [3.0-22.2], log-rank p=0.004); overall mortality (21.5% [13.5-29.5] vs 32.4% [23.4-41.4], difference between groups 10.9% [0.6-21.2], log-rank p=0.045); and disease-specific mortality (5.6% [1.2-10.0] vs 16.2% [6.1-23.3], difference between groups 10.6% [2.5-18.7], log-rank p=0.01). Side-effects were mainly localised to the bladder. INTERPRETATION BCG-induced inflammation might increase the permeability of the bladder mucosa such that mitomycin can reach the target tissue more easily and exert its anticancer effect.

Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial non-muscle invasive bladder cancer: a randomised controlled trial

BACKGROUND The clinical effect of intravesical instillation of chemotherapy immediately after transurethral resection of bladder tumours (TURBT) has recently been questioned, despite its recommendation in guidelines. Our aim was to compare TURBT alone with immediate post-TURBT intravesical passive diffusion (PD) of mitomycin and immediate pre-TURBT intravesical electromotive drug administration (EMDA) of mitomycin in non-muscle invasive bladder cancer. METHODS We did a multicentre, randomised, parallel-group study in patients with primary non-muscle invasive bladder cancer in three centres in Italy between Jan 1, 1994, and Dec 31, 2003. Patients were randomly assigned to receive treatment by means of stratified blocked randomisation across six strata. Patients and physicians giving the interventions were aware of assignment, but it was masked from outcome assessors and data analysts. Patients were randomly assigned to receive TURBT alone, immediate post-TURBT instillation of 40 mg PD mitomycin dissolved in 50 mL sterile water infused over 60 min, or immediate pre-TURBT instillation of 40 mg EMDA mitomycin dissolved in 100 mL sterile water with intravesical 20 mA pulsed electric current for 30 min. Our primary endpoints were recurrence rate and disease-free interval. Analyses were done by intention to treat. Follow-up for our trial is complete. This study is registered with ClinicalTrials.gov, number NCT01149174. FINDINGS 124 patients were randomly assigned to receive TURBT alone, 126 to receive immediate post-TURBT PD mitomycin, and 124 to receive immediate pre-TURBT EMDA mitomycin. 22 patients were excluded from our analyses because they did meet our eligibility criteria after TURBT: 11 had stage pT2 disease and 11 had carcinoma in situ. Median follow-up was 86 months (IQR 57-125). Patients assigned to receive EMDA mitomycin before TURBT had a lower rate of recurrence (44 [38%] of 117) than those assigned to receive PD mitomycin after TURBT (70 [59%] of 119) and TURBT alone (74 [64%] of 116; log-rank p<0·0001). Patients assigned to receive EMDA mitomycin before TURBT also had a higher disease-free interval (52 months, IQR 32-184) than those assigned to receive PD mitomycin after TURBT (16 months, 12-168) and TURBT alone (12 months, 12-37; log-rank p<0·0001). We recorded persistent bladder symptoms after TURBT in 18 (16%) of 116 patients in the TURBT-alone group (duration 3-7 days), 37 (31%) of 119 in the PD mitomycin post-TURBT group (duration 20-30 days), and 24 (21%) of 117 in the EMDA mitomycin pre-TURBT group (duration 7-12 days); haematuria after TURBT in eight (7%) of 116 patients in the TURBT-alone group, 16 (13%) of 119 in the PD mitomycin post-TURBT group, and 11 (9%) of 117 in the EMDA mitomycin pre-TURBT group; and bladder perforation after TURBT in five (4%) of 116 patients in the TURBT-alone group, nine (8%) of 119 in the PD mitomycin post-TURBT group, and seven (6%) of 117 in the EMDA mitomycin pre-TURBT group. INTERPRETATION Intravesical EMDA mitomycin before TURBT is feasible and safe; moreover, it reduces recurrence rates and enhances the disease-free interval compared with intravesical PD mitomycin after TURBT and TURBT alone. FUNDING None.

Single immediate preoperative intravesical instillation of electromotive mitomycin-C for low risk superficial bladder cancer: A prospective randomized study

5027 Background: To evaluate and compare the results of electromotive mitomycin-C (MMC) instillation administered before transurethral resection (TUR) with TUR alone or TUR plus single immediate MM...

Sequential Bacillus Calmette Guèrin and electromotive mitomycin-C versus Bacillus Calmette Guèrin alone for high-risk superficial bladder cancer: A prospective controlled study

4539 Background: Intravesical bacillus Calmette-Guèrin (BCG) and mitomycin C (MMC) are a theoretically attractive combination for the treatment of high risk superficial bladder cancer. We conducted a prospective, controlled study comparing BCG with sequential BCG + electromotive delivery MMC in patients with T1 bladder cancer. METHODS Following transurethral resection and multiple biopsies we randomized 175 patients with T1 bladder cancer into 2 groups. Group I received BCG 81 mg; 6 weekly instillations. Group II received sequential BCG and electromotive (intravesical electric current; 20 mA for 30 min.) MMC at weekly intervals thus: (BCG, BCG, MMC) x 3, totaling 6 BCG and 3 MMC instillations. Non responders received repeat courses at 3 months. All complete responders underwent maintenance regimens of monthly instillations. Group I: 10 BCG treatments. Group II: (MMC, MMC, BCG) x 3, treatments. RESULTS Group I vs Group II: median (IQR or 95% CI). Follow up (months): 64 (38-82) vs 71 (49-87); p = 0.054 Recurrence: 47% (36-58) vs 28% (19-39); p = 0.013 Months to Recurrence: 11 (6-19) vs 20 (16-33); p = 0.001 Progression: 20% (12-30) vs 14% (7-22); p = 0.312 Months to Progression: 17 (10-21) vs 46 (21-58); p = 0.002 % 5-years mortality by any cause: 11.6 (5.7-20.3) vs 4.5 (1.2-11.1); p = 0.099 % 5-years mortality by bladder cancer: 9.3 (4.1-17.5) vs 1.1 (0.02-6.1); p = 0.017 Side effects were numerous but mainly localized to the bladder. There were no treatment related deaths nor episodes of serious illness nor bladder contractures. CONCLUSIONS Intravesical sequential BCG/electromotive MMC is superior to BCG alone in the treatment of high risk bladder cancer. [Table: see text].